Little is known about the incidence and clinical outcomes of infective endocarditis (IE) involving native valves in Asian countries. This nationwide study investigated epidemiologic features and in-hospital mortality associated with IE in adults (age ≥18 years) based on Taiwan’s National Health Insurance database from 1997 through 2002. Of 7,240 enrolled patients with IE involving native valves, the mean age was 53 ± 19 years and 70% were men. The mean annual crude incidence was 7.6 per 100,000 inhabitants. The incidence was significantly higher in men than in women (10.4 vs 4.6 per 100,000; p <0.001). The incidence of IE increased steadily with age, ranging from 3.8 per 100,000 persons in patients <30 years of age to 33 per 100,000 persons in patients ≥80 years of age (p <0.001). Staphylococcal (32%) and streptococcal species (61%) were the most common causative pathogens. The mean in-hospital mortality rate was 18%. Multivariate analysis showed that male gender, older age (≥50 years), diabetes mellitus, heart failure, neurologic complications, renal insufficiency, respiratory failure, shock, and Staphylococcus species as the causative microorganism were independent predictors of in-hospital mortality. In conclusion, this Taiwanese study revealed a high incidence of IE in men and elderly subjects. The in-hospital mortality rate remained high. Patients with IE who also developed shock and respiratory failure were the most likely to have a poor outcome.